rs763841075

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_StrongBS1_Supporting

The NM_002087.4(GRN):c.415T>C(p.Cys139Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000142 in 1,612,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GRN
NM_002087.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 5.06

Publications

43 publications found

Variant links:

Genes affected

GRN (HGNC:4601): (granulin precursor) Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis. [provided by RefSeq, Jul 2008]

GRN Gene-Disease associations (from GenCC):

frontotemporal dementia and/or amyotrophic lateral sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
neuronal ceroid lipofuscinosis 11
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P, Orphanet

GRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000146 (214/1461708) while in subpopulation MID AF = 0.00416 (24/5768). AF 95% confidence interval is 0.00287. There are 0 homozygotes in GnomAdExome4. There are 111 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4 link	c.415T>C	p.Cys139Arg	missense_variant	Exon 5 of 13	ENST00000053867.8	NP_002078.1	P28799-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 link	c.415T>C	p.Cys139Arg	missense_variant	Exon 5 of 13	1	NM_002087.4	ENSP00000053867.2		P28799-1

Frequencies

GnomAD3 genomes

AF:

0.0000992

AC:

AN:

151196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000179

AC:

AN:

251476

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000146

AC:

214

AN:

1461708

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000313

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000124

AC:

138

AN:

1111848

Other (OTH)

AF:

0.000182

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000992

AC:

AN:

151196

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

73754

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41030

American (AMR)

AF:

0.000132

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.000209

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10458

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67838

Other (OTH)

AF:

0.000484

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000212

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in association with a wide spectrum of later-onset ALS-FTLD neurological phenotypes (Brouwers et al., 2008; Piaceri et al., 2014; Redaelli et al., 2018); Asymptomatic carriers of this variant have been found to have lower serum/plasma PGRN levels compared to controls but not as low as in cases with null variants, suggesting a partial loss of function (Sleegers et al., 2009; Finch et al., 2009; Guven et al., 2019); Published functional studies demonstrate that this variant leads to reduced neurite outgrowth stimulating activity compared to wild type (Wang et al., 2010); This variant is associated with the following publications: (PMID: 32772750, 24503614, 27997711, 19158106, 19288468, 30475763, 18565828, 25352065, 23392204, 26444794, 18314228, 20020531, 23742080, 25575133, 26652843, 27632209, 23684369, 22647257, 20028451, 23724906, 21800185, 31031559) -

Sep 17, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP4 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11

Uncertain:2

Oct 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 139 of the GRN protein (p.Cys139Arg). This variant is present in population databases (rs763841075, gnomAD 0.04%). This missense change has been observed in individual(s) with frontotemporal dementia or Alzheimer disease (PMID: 21800185, 23724906, 24503614, 27632209, 27997711, 34162492, 34435519). ClinVar contains an entry for this variant (Variation ID: 589965). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GRN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GRN function (PMID: 20028451, 22781549, 26652843). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Sep 13, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.C139R variant (also known as c.415T>C), located in coding exon 4 of the GRN gene, results from a T to C substitution at nucleotide position 415. The cysteine at codon 139 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been detected in several individuals with frontal lobe temporal dementia, progressive late onset dementia, and corticobasal syndrome (Brouwers N et al. Neurology, 2008 Aug;71:656-64; Finch N et al. Brain, 2009 Mar;132:583-91; Bernardi L et al. Neurobiol. Aging, 2009 Nov;30:1825-33; Gómez-Tortosa E et al. Eur. J. Neurol., 2013 Sep;20:1319-24; Bagnoli S et al. Cell. Mol. Neurobiol., 2012 Jan;32:13-6; Rodríguez-Rodríguez E et al. Parkinsonism Relat. Disord., 2013 Aug;19:768-9; Guven G et al. PLoS ONE, 2016 Sep;11:e0162592). In vitro functional studes have shown this variant is likely to impair the physiological processing of the protein and structural modeling predicts this variant has a destabilizing effect on the protein (Brouwers N et al. Neurology, 2008 Aug;71:656-64; Wang J et al. J. Neurochem., 2010 Mar;112:1305-15; Karch CM et al. Neurobiol. Aging, 2016 Feb;38:215.e1-12). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

GRN-related disorder

Uncertain:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GRN c.415T>C variant is predicted to result in the amino acid substitution p.Cys139Arg. This variant has been reported in multiple unrelated individuals with various neurodegenerative conditions including Alzheimer disease, frontotemporal dementia, semantic dementia, progressive nonfluent aphasia, and corticobasal syndrome (Bernardi et al. 2008. PubMed ID: 18314228; Bagnoli et al. 2011. PubMed ID: 21800185; Antonell et al . 2012. PubMed ID: 22647257; Piaceri et al. 2014. PubMed ID: 24503614; Redaelli et al. 2017. PubMed ID: 27997711; Guven et al. 2016. PubMed ID: 27632209). In one report, this variant was detected in an individual with progressive nonfluent aphasia but was also reported in two unaffected family members age 66 and 42 years of age (Antonell et al. 2012. PubMed ID: 22647257). While mutant GRN protein levels did not differ from non-carrier family members, in an axonal outgrowth assay, the p.Cys139Arg mutated PGRNs did not stimulate neurite outgrowth (Wang et al. 2009. PubMed ID: 20028451). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD and has been consistently classified as uncertain in ClinVar. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Uncertain:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;T;.;T;T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T;T;T;T;T;T

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;.;H

PhyloP100

5.1

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-11

D;.;.;.;.;.;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;.

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.94

MVP

1.0

MPC

1.2

ClinPred

0.99

GERP RS

4.2

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.98

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over